1. Field of the Invention
The present invention relates to a method for the monitoring and control of a freeze drying process and, more particularly, to the use of surface heat flux measurement for such monitoring and control.
2. Description of the Background Art
Traditionally only temperature is measured from various points of a system to monitor and control the freeze drying process. However, knowing temperature alone is not enough to control and optimize the freeze drying process, since temperature change is the end result of a heat transfer event. In most cases, the moment an undesirable temperature change is detected, it is too late to make any correction to fix it.
Traditional freeze drying process control is inefficient open loop control due to limited feedback from product temperature and only being able to control the heat transfer fluid temperature from the point at which it flows into the shelf stack. Depending on the different product loads (i.e.: quantity, size and fill of product or vials) as well as the equipment construction (i.e.: shelf construction, fluid pump size and flow rate, etc.) the actual shelf surface temperature varies, although the inlet fluid temperature remains constant. In addition, the heat transfer coefficient changes with vacuum level and product container. This means that the same inlet shelf temperature may result in different product temperatures and therefore different freezing and drying results. The missing link in this control loop is heat flux measurement between shelf and product.
Freezing Step
Freezing, in the freeze drying process, consists of a nucleation process and a post nucleation thermal treatment to produce an ice crystal structure that concentrates the previously dissolved product into a fixed matrix between the ice crystals. Typically, nucleation occurs in a random fashion due to differences in heat transfer resulting in inconsistent crystallization across a batch which results in different drying performance and inconsistent product results. Proper crystal structure allows an elegant cake to be produced which also reduces the total drying time. To produce a consistent crystal structure that aids drying, controlled nucleation is combined with a proper thermal treatment.
Temperature sensors do not provide the feedback required for consistent crystallization process control. For example, during freezing the product may not change temperature, such as during removing latent heat in the freezing step. Although the product temperature doesn't change, there is a significant heat transfer event taking place.
During post nucleation latent heat removal, the speed of heat transfer has a major impact on ice crystal size, orientation and distribution. The ice crystal structure dramatically influences the drying performance and final product appearance. Measuring the heat flow enables better control of the freezing process. This method enables control of the shelf temperature during thermal events when there is no product temperature change.
Drying Step
Drying can be further divided into primary drying and secondary drying steps. Primary drying is a sublimation process where ice in a frozen product turns directly into vapor which is then condensed on a cold condensing surface leaving behind a matrix of concentrated product in the vial or tray on the shelf. Secondary drying is a desorption process. The remaining moisture in the concentrated product matrix is reduced to a level that is best for product long term stability.
Typically, optimized drying requires a process to efficiently remove water without losing the product matrix structure created during the freezing step. The key here is keeping the product at the maximum allowed temperature while still below the critical temperature. The critical temperature is the product temperature above which the product melts and/or the matrix collapses.
There may also be applications when some form of collapse is required. The process can also be monitored, optimized and controlled for these applications.
From a process control perspective, cycle optimization results in a shelf temperature and chamber pressure combination that balances the heat and mass flow and maintains the product at its optimum temperature. Traditionally this is a very challenging task which involves a multi-step trial and error approach, since measuring temperature and pressure alone cannot solve the heat and mass flow balance problem.
Some methods that are currently used for in-process measurement in freeze drying systems are:
MTM—An in-process technique that only calculates the product temperature based on pressure rise measurements. This technique is limited to critical batch sizes and does not provide mass flow information. It can only provide intermittent measurement no faster than every half hour. Measurements are limited to the first half of a cycle as it loses its accuracy in the second half of the cycle.
TDLAS—Tunable Diode Laser—An in-process technique that measures mass-flow through a duct using a laser. This is an expensive technique that works only during the drying stage of the freeze drying process. Only equipment with an external condenser can be fitted with TDLAS. The instrument itself significantly extends the length of the vapor duct and limits the maximum vapor flow rate through the duct to the condenser.
Two container differential heat flux measurement—described in U.S. Pat. No. 5,367,786 is a heat flux based process control method which measures the difference in heat flux between a process monitoring container and a reference container on a single heating or cooling surface. Since no two containers are identical, especially glass vials used in the apparatus, there is a limit to the accuracy of the measurement. Placement of an empty reference container among the sublimating product containers significantly changes the heat transfer mechanism on both measuring and referencing points. As heat transfer can happen between an empty reference container and product containers, measuring accuracy of the differential heat flux can be compromised. Placing a metal foil based radiant shield between two containers further changes the heat transfer mechanism between heating or cooling surfaces. The fundamental limitation of this method is that it significantly changes the heat transfer mechanism, which the method is trying to measure. In a production scale system, placement of the measuring apparatus is impractical. It also requires a temperature probe being directly placed in a product container which is considered invasive. In view of the above limitations, this method has never been widely adopted in either lab or production applications.
Crystal structure may very well be the most important physical property to control in the freeze drying process. However, most of the concentration on improving the freeze drying process has centered on the sublimation or primary drying phase. Since the sublimation process is the longest step in freeze drying, improvements can result in higher output and better product consistency.
Placing vials on a shelf and lowering the shelf temperature, as is done in the majority of freeze dryers, results in non-homogeneous freezing of the product in the vials due to different degrees of super-cooling. The result is varying crystal structures across the vials caused by different nucleation temperatures and rates. The variation in crystal structure results in varying sublimation rates and therefore product inconsistencies.
Primary drying is the longest step of the freeze drying process. Most of the effort for process improvement has focused on measuring and controlling the product temperature as close to its critical point as possible to shorten the cycle. However, without proper ice structures in the frozen product there is a limit to how much faster cycles can be performed without compromising end product quality. Producing a better product crystal structure, through proper freezing, can result in both higher yields due to more uniform cake structure and shorter primary drying cycles due to reduced cake resistance. In general, larger crystals are easier to freeze dry, while small crystals impede sublimation thus lengthening the process. The speed of freezing has a direct effect on the size and type of crystal. Faster freezing produces a smaller crystal, while slower freezing produces are larger crystal. Changes in freezing rate result in varying crystal structures.
The challenge to creating a proper crystal structure is that the typical freezing process does not control the heat flow to the product and therefore crystal growth varies. Placing vials on a shelf and lowering the shelf temperature, as is done in the majority of freeze dryers, results in heterogeneous nucleation across the batch and heterogeneous crystal growth in the vials. The randomness of freezing is due to different degrees of super-cooling and variations in heat flow during the ice crystal growth process. It is important to understand that the rate of crystal growth varies even though the rate of shelf temperature change may not.
The main challenge during this stage of freezing is that nucleation is random and product temperature change does not occur during the phase change of free water from liquid to solid. The rate of crystal growth is dependent on the heat transfer efficiency of the equipment. The heat flow changes significantly as the shelf is cooled and the product freezes. The changing heat flow results in an inconsistent ice structure inside the vial and across the batch.
In order to create the most consistent crystal structure in the vial and across the batch a common starting point and a method for controlling the rate of crystal growth is required. To improve on the current process of freezing, a method for controlled nucleation combined with a method for monitoring and controlling the heat flow during crystallization is required. Producing a controlled nucleation event provides a consistent starting point across the batch for freezing, while controlling the heat flow during crystal formation enables growth of more ideal ice structures. The goal for nucleation is to have all of the vials nucleate at the same time, same temperature and at the same rate. The result will be a consistent starting point across the batch for controlling crystal growth during crystal formation inside the vial.
It is important to point out, that controlled nucleation by itself does not significantly reduce primary drying times. Controlled nucleation provides a homogeneous starting point, but it is proper control of super-cooling and control of post-nucleation crystal growth that can produce a reduction in primary drying time. For example, sucrose super-cooled to −10 C, nucleated, and then cooled rapidly will result in a small crystal structure and minimal improvement in primary drying times. Therefore, post-nucleation thermal treatment is critical to a uniform and freeze drying friendly ice structure inside the vial.